Methods for prophylactic treatment of cardiovascular disease with inhibitor of cortisol synthesis

ABSTRACT

Ketoconazole and related substances which are inhibitors of cortisol synthesis can be administered to prophylactically treat cardiovascular disease, such as coronary artery disease, artiosclerotic manifestations, and stroke.

This application is a divisional of Ser. No. 09/211,282 filed Dec.14,1998, U.S. Pat. No. 6,166,017, which is a continuation of Ser. No.08/776,983 filed Feb. 6,1997, U.S. Pat. No. 5,849,740, which is a 371PCT/SE94/00729 filed Aug. 9, 1994.

The present invention relates to the use of ketoconazole or moleculesresembling ketoconazole but with some side-chains, not affecting thebiological activity compared to ketoconazole, changed for manufacturingdrugs for treatment of diabetes mellitus type II.

The drug ketoconazole (Trade name Fungora™) is a well-documented drugfor treatment of fungal infections. The process of making ketoconazoleis well known and described. In this invention Fungoral™ capsules aimedat oral administration should be used. This means that Fungoral™ shouldbe administered the same way (oral) and in the same composition that isalready well-known on the market for treatment of fungal infections theoral route. Therefor it is not considered necessary to further describethe process of making Fungora™. For the same reason it is not considerednecessary to give a full, clear, concise and exact term of this drug,since it is already well-known for persons skilled in the art ofmedicine.

The drug comprising ketoconazole (Trade name Fungoral™) and chemicallyclosely related substances, the mode of operation of which is toinfluence the normal cortisol synthesis in the adrenal glands in such away that the production of biologically perfectly acting cortisol ispartly inhibited, is intended to be used for medical treatment ofdiabetes mellitus type II in men and women as well as for counter-actingthe risk factors which are parts of the Metabolic Syndrome (also knownas “the deadly quartet” or “Syndrome X” or the “Insulin ResistanceSyndrome”), which is characterised by an accumulation of risk factorsfor cardiovascular disease, stroke and diabetes mellitus type II, i.e.insulin resistance, hyperinsulinemia, abdominal obesity, (caused by anaccumulation of intra-abdominal fat), elevated serum lipids, and raisedblood pressure, as well as reducing the risk of development of thesediseases.

In this new invention ketoconazole small be administered the oral routein doses of 100-800 mg daily. The drug can be administered once orseveral times daily. At present a dose of 400 mg administered in theevening has been proven to be the best mode. However, we also claim thatadministration at other points of time, and in other doses (100-800 mg)can be equally effective.

Since ketoconazole is also inhibiting the normal production oftestosterone in men, it is possible that this sex needs a certain amountof testosterone supplementation when treated with ketoconazole, to havean optimal effect of the treatment.

We have investigated a group of people with diabetes mellitus type II.They have been treated with ketoconazole during 2 and 6 weeks,respectively. Investigations before and after treatment have shown adecrease in blood glucose measured either in the fasting state or at 2hours after an intraveneus glucose infusion, and most important, aremarkable improvement of insulin sensitivity. More exact data fromthese studies are given in the tests described below.

Since a decreased insulin sensitivity is a central part of “Themetabolic syndrome”, also known as “The deadly quartet”, “Syndrome X” orthe “Insulin Resistance Syndrome” we also claim that fungoral treatmentto people with risk factors according to this syndrome should beexpected to be effective also for treatment of these specific riskfactors (abdominal obesity, hypertension, elevated blood lipids) as wellas for decreasing the risk for diseases caused by these risk factors(Cardiovascular disease such as coronary artery disease, otherarteriosclerotic manifestations including stroke).

The mechanism of the action of ketoconazole is that the substanceinfluence the cortisol synthesis of the adrenal glands in such a waythat a sub-fraction of a biologically non-perfect substance similar tocortisol, so called “crippled cortisol”, is formed instead of the normalcortisol molecule.

The cortisol antagonistic effect of the drug is considered to have acentral importance for the positive effects on the risk factorsmentioned above, decreasing the metabolic activity of fat inside theabdominal cavity, which in turn leads to a decreased fat infiltration ofthe liver, improving the glucose homeostasis over the liver andperipherally in the tissues in turn leading to improvement of diabetesmellitus type II (decreasing blood glucose and increasing insulinsensitivity), reducing the serum lipids through improvement of theregulating mechanisms in the liver and also inhibiting cholesterolsynthesis by a direct effect on the adrenal glands. A positive effect onthe blood pressure can also be expected via the cortisol-antagonisticeffect.

The scientific basis for these effects can be explained by an inhibitionof the physiologically increased cortisol secretion rate that is knownto be present under the conditions described above. (The metabolicsyndrome and its synonyms described above). This increased cortisolsecretion can per se explain all the parts of the syndrome describedincluding the development of diabetes mellitus type II. The scientificexplanation for the beneficial effects of ketoconazole on the treatmentof diabetes mellitus type II is its effects of decreasing the secretionof biologically active cortisol.

The basic substance is ketoconazole in the chemical form which is knownand well documented in the literature. This substance can be furtherchemically modified while maintaining the same biological effects byexchange of different molecular side chains. These substances similar toketoconazole can then be expected to have similar and/or better effectson the cortisol inhibiting mechanism, which is described above.

A positive effect on the treatment of patients with diabetes mellitustype II with ketoconazole has been shown in that after theadministration of ketoconazole a reduction of the insulin insensitivity(resistance), which is often associated with this disease, has beenmeasured. This has been measured as an improved (i.e. reduced) insulinresistance measured with a so called euglychemic glucose clamp method.Thus, the examined patients have improved with regard to their diabetes,measured in the above described way, which in parallell also haveresulted in lower blood glucose after treatment compared to beforetreatment.

The category of patients, that would have an especially good use ofketoconazole are patients with diabetes mellitus type II with insulininsensitivity and despite treatment with usual anti-diabetic drugsand/or insulin still have remaining elevated glucose values in the bloodin fasting condition as well as after a meal. The investigated patientshad decreased insulin sensitivity compared to healthy persons, measuredby euglychemic glucose clamp. Supply of ketoconazole to this category ofpatients has been shown to have a positive and specific effect on theinsulin insensitivity in such a way that their diabetes mellitus type IIwas improved. This was measured as improved insulin sensitivity andlower blood glucose.

Other positive effects have also been detected among these patients:Reduced cholesterol levels in the plasma as well as decreasing bloodpressure values.

Results of Clinical Tests of Women with Diabetes Mellitus Type II,Treated with Ketoconazole.

Group 1 consists of 3 patients (mean age: 46 years) treated withketoconazole for 2 weeks, administered orally 22.00 in the evening inthe dose of 400 mg.

Group 2 consists of 5 patients (mean age: 51 years) treated withketoconazole for 6 weeks, administered orally 22.00 in the evening inthe dose of 400 mg.

Results are expressed as mean values within groups.

Group 1 Group 2 Variables studied Before t. After t. Before t. After t.Fasting blood 10.20 8.77 7.20 7.10 glucose (mmol/L) Blood glucose 9.737.90 6.48 5.76 (mmol/L) 2 hours after start of an i.v. glucose in-fusion GIR (glucose in- 0.9 1.85 2.97 4.32 fusion rate during euglycemicglucose clamp expressed as mg glucose per minute divided by lean bodymass), indicating insulin sensitivity Fasting serum 5.80 5.67 4.80 4.10total cholesterol (mmol/L) Systolic blood 140 135 125 123 pressure (mmHg) measured after 5 min. in supine position. 2 measurements averagedDiastolic blood 70 70 75 72 pressure (mm Hg) measured after 5 min. insupine position. 2 measurements averaged Serum-ASAT 0.36 0.33 0.26 0.25(μkat/L) Serum-ALAT 0.61 0.52 0.40 0.37 (μkat/L)

The use of ketoconazole or molecules resembling ketoconazole but withsome side-chains, not affecting the biological activity compared toketoconazole, changed, for the manufacture of drugs for medicaltreatment of diabetes mellitus type II as well as for counteracting theother risk factors being part of the Metabolic Syndrome (also known as“the deadly quartet” or “Syndrome X” or the “Insulin ResistanceSyndrome”).

What is claimed is:
 1. A method for the prophylactic treatment ofcardiovascular disease and arteriosclerotic manifestations, which methodcomprises the steps of: providing a cortisol inhibitor; andadministering an effective amount of said inhibitor to a patient in needthereof.
 2. The method according to claim 1, wherein said inhibitor isketoconazole, or derivatives thereof having a corresponding biologicalactivity as compared to ketoconazole, or a mixture of both.
 3. Themethod according to claim 1, wherein the daily dose of said inhibitor isbetween 100 and 800 mg.
 4. The method according to claim 3, wherein 400mg of said inhibitor is administered to the patient in the evening.
 5. Amethod for the prophylactic treatment of cardiovascular disease andarteriosclerotic manifestations, which method comprises: providing acortisol inhibitor; providing testosterone; and co-administering to amale patient in need thereof an amount of said inhibitor effective todecrease the amount and/or activity of cortisol in said patient and anamount of said testosterone effective to normalize any decrease in saidpatient's testosterone caused by said administration of said inhibitor.6. The method of claim 5, wherein said treatment is for cardiovasculardisease that is manifest as coronary artery disease.
 7. The method ofclaim 5 wherein said treatment is for an arteriosclerotic manifestationpresenting s stroke.
 8. The method of claim 1 wherein said treatment isfor cardiovascular disease that is manifest as coronary artery disease.9. The method of claim 1 wherein said treatment is for anarteriosclerotic manifestation presenting as stroke.